Transcript Microbicides

Novel Intravaginal Delivery of
Antiretroviral-based
Microbicides for HIV Prevention
Simi Gunaseelan, Ph.D.
Assistant Professor of Pharmaceutical Sciences
Ben and Maytee Fisch College of Pharmacy The
University of Texas at Tyler
Texas, USA
HIV/AIDS research
Global HIV / AIDS estimates published by
UNAIDS (by end of 2012)
Viral Attack after Sexual Exposure to HIV
This is how
HIV gets in.
Now how do
we stop it?
Potential Mechanisms for HIV Transmission
across Vaginal and Rectal Mucosal Epithelium
Viral attack after sexual exposure to HIV
How to Prevent Viral Attack Pre - & PostSexual Exposure to HIV?
With an HIV vaccine likely to be years
away, encouraging the development of
new preventative technologies such as
Pre-Exposure Prophylaxis and
Post-Exposure Prophylaxis
(such as “Microbicides”) ……….….
PrEP & Microbicides –
New Hope for HIV Prevention
Pre-Exposure Prophylaxis (PrEP) strategies:
Drug administered orally or topically
(including “microbicides”) to prevent HIV
infection by any of several routes of
transmission
PrEP & Microbicides –
New Hope for HIV Prevention
“Microbicides”, a subset of PrEP strategies,
are drug products applied topically to the
vaginal or rectal mucosa in a variety of
formulations (gel, cream, suppository, film,
sponge, foam, vaginal or rectal ring - that
release the active ingredient gradually) prior
to sexual intercourse, for the purpose of
preventing or substantially reducing sexually
transmitted infections, including HIV, in a
sexually receptive partner. These topical
microbicide products might be applied to
condoms or directly to the genitals
(vagina or rectum) to block HIV
How do Microbicide Work Pre - & PostSexual Exposure to HIV?
Current HIV Microbicide Formulations
At present there is no agreed “gold
standard” around microbicide formulation
Vaginal Gel with Applicator
Recent research focuses on highly potent
and specific anti-retroviral based
microbicides (formulated as primary dosage
forms e.g., vaginal gels or alternative dosage
forms such as fast dissolve films and tablets)
Vaginal Film
Vaginal Ring with pods
Vaginal Tablet
Vaginal Tablet Applicator
Limitations of Current HIV Microbicide
Delivery (Formulation) Technologies
Current Diffusion /Hydrolysis /Dissolution – based
Microbicide Delivery Technologies
Vaginal Tablet
Dissolution
Degradable Matrix
With Drug Entrapped
Released
Drug
Degraded
Matrix
Un-degraded
Matrix
Diffusion
Vaginal Gel
Released
Drug
Un-degraded
Matrix
Vaginal Film
Current Problems:
 Microbicide release is more Dependent on the Size, Structure, and
Physicochemical properties of a Microbicide rather than on the ‘Intrinsic
Performance of the Delivery System’
 Stability of microbicides in Aqueous Gels and Films – ‘Big Challenge’ if
drug is unstable in water
‘Novel’ Subliming Solid-based Intravaginal
Microbicide Delivery Formulation
Sublimed
Vapors
Released
Drug
Sublimation
Sublimable Matrix
With Drug Entrapped
37 °C
Un-sublimed
Matrix
Advantages:
 Drug release NOT due to conventional hydrolysis or
dissolution of matrix material or diffusion of water into or
drug out of a matrix
 Release of Microbicide is INDEPENDENT of the Size,
Structure, and Physicochemical properties of the
Microbicide
‘Novel’ Vaginal
Formulations
‘Novel’ Subliming Solid-based Intravaginal
Microbicide Delivery Formulation
Sublimed
Vapors
Released
Drug
Sublimation
Sublimable Matrix
With Drug Entrapped
37 °C
Un-sublimed
Matrix
Sublimation Mechanism:
‘This process entails incorporation of drug into a matrix, and
subsequent matrix erosion, where, release of drug from
chemically inert and water insoluble hydrophobic matrices
occur by surface erosion achieved through sublimation (direct
conversion of solid to a gas) of matrix, allowing newly exposed
drug particles to be delivered to the environment of the
intravaginal administration site’
‘Novel’ Vaginal
Formulations
What can these ‘Novel’ Intravaginal
Microbicide Delivery Formulations do?
Sublimed
Vapors
Released
Drug
Sublimation
Sublimable Matrix
With Drug Entrapped
37 °C
Un-sublimed
Matrix
Unique Performances of Subliming Solid Matrices:
 Provide continuous and controlled delivery of a broad
structural array of HIV microbicides (dissimilar), at rates
independent of their size and physicochemical properties
 Stabilize ‘unstable microbicides’
 Extend antiviral efficacy of microbicides of high clinical
importance by sustained release from subliming solids
‘Novel’ Vaginal
Formulations
Choice of Antiretroviral-based Microbicides
for ‘Novel’ Delivery System Evaluation
18 amino acid – C5A Peptide
Vaginal Defence Enhancer
Antiretroviral
NRTI
Antiretroviral
NRTI
Emtricitabine
Tenofovir
Antiretroviral Microbicides:
 Emtricitabine (un-charged, highly water soluble) and Tenofovir
(charged, poorly water soluble) – which have achieved clinical
confirmation of microbicidal efficacy in recent CAPRISA
(topical- Vaginal Gel) and iPrEx (oral) administration trials
 C5A Peptide (charged, hydrophobic, low aqueous solubility) peptide microbicide with promising pre-clinical results
‘Novel’ Vaginal
Formulations
In Vitro Release Rates of Microbicides were
Independent of Physicochemical Properties
HMCS
Matrix
PF-11
Matrix
Subliming Solid Matrices were Non-Toxic to
HIV-1 Target Cells
Human
PBMCs
Human
T-Lymphocytes
Human
Macrophages
Human Ectocervical
Tissue
Subliming Matrices Prolonged Antiviral
Activity in Human Macrophages & TZM Cells
Tenofovir /
TZM Cells
Tenofovir /
Human
Macrophages
Emtricitabine /
Human
Macrophages
Emtricitabine /
TZM Cells
C5A / TZM
Cells
C5A /
Human
Macrophages
Subliming Matrices Prolonged Antiviral
Activity in Human Ectocervical Explants
This Work Resulted in 2 Publications
 Simi Gunaseelan, Philippe Gallay, Michael Bobardt,
Charlene S. Dezzutti, Timothy Esch and Richard
Maskiewicz. Sustained local delivery of structurally
diverse HIV-1 microbicides released from sublimation
enthalpy controlled matrices. Pharmaceutical Research,
2012; 29, 3156-3168.
 Richard Maskiewicz, Michael Bobardt, Udayan Chatterji,
Simi Gunaseelan, Charlene S. Dezzutti, Francois Penin and
Philippe A. Gallay. Sublimable C5A delivery provides
sustained and prolonged anti-HIV microbicidal activities.
Antimicrobial Agents and Chemotherapy, 2012; 56, 33363343.
Research Collaborations
Dr. Charlene S. Dezzutti
(University of Pittsburgh, PA)
Dr. Philippe A. Galla
(Scripps Research Institute, CA)
Dr. Richard Maskiewicz
(Loma Linda University, CA)